Stable, uncleaved HIV-1 envelope glycoprotein gp140 forms a tightly folded trimer with a native-like structure
Ha, Heather Jiwon
MetadataShow full item record
CitationKovacs, James M., Erik Noeldeke, Heather Jiwon Ha, Hanqin Peng, Sophia Rits-Volloch, Stephen C. Harrison, and Bing Chen. 2014. “Stable, Uncleaved HIV-1 Envelope Glycoprotein Gp140 Forms a Tightly Folded Trimer with a Native-like Structure.” Proceedings of the National Academy of Sciences 111 (52): 18542–47. doi:10.1073/pnas.1422269112.
AbstractThe HIV-1 envelope spike [trimeric (gp160)(3), cleaved to (gp120/gp41)(3)] is the mediator of viral entry and the principal target of humoral immune response to the virus. Production of a recombinant preparation that represents the functional spike poses a challenge for vaccine development, because the (gp120/gp41)(3) complex is prone to dissociation. We have reported previously that stable HIV-1 gp140 trimers, the uncleaved ectodomains of (gp160)(3), have nearly all of the antigenic properties expected for native viral spikes. Because of recent claims that uncleaved gp140 proteins may adopt a nonnative structure with three gp120 moieties "dangling" from a trimeric gp41 ectodomain in its postfusion conformation, we have inserted a long, flexible linker between gp120 and gp41 in our stable gp140 trimers to assess their stability and to analyze their conformation in solution. The modified trimer has biochemical and antigenic properties virtually identical to those of its unmodified counterpart. Both forms bind a single CD4 per trimer, suggesting that the trimeric conformation occludes two of the three CD4 sites even when a flexible linker has relieved the covalent constraint between gp120 and gp41. In contrast, an artificial trimer containing three gp120s flexibly tethered to a trimerization tag binds three CD4s and has antigenicity nearly identical to that of monomeric gp120. Moreover, the gp41 part of both modified and unmodified gp140 trimers has a structure very different from that of postfusion gp41. These results show that uncleaved gp140 trimers from suitable isolates have compact, native-like structures and support their use as candidate vaccine immunogens.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41542743
- HMS Scholarly Articles